When administered chronically to laboratory animals, certain cationic amphiphilic drugs induce a phospholipid storage disorder in the alveolar macrophage of the lung. This laboratory has been studying the effects of the administration of one such drug, chlorphentermine, on properties and functions of the rat alveolar macrophage. This proposal describes studies which will continue this work. One feature of this disorder is the intra-alveolar accumulation of enlarged macrophages. Experiments are presented which will provide information as to whether this accumulation originates from an increased influx of cells into the alveoli. To study this, the rate of appearance of new cells into the alveoli in treated rats will be compared with that found in controls. The intra-alveolar accumulation of cells could result, instead, from a decreased clearance. Therefore, the in vivo adherence of macrophages to the alveolar epithelium will be examined since the loss of such macrophage-epithelial association could lead to an impairment in the movement of the cells from the alveoli. As one measure of the effects of chlorphentermine treatment on the alveolar macrophage, the role of reactive oxygen in the function and toxicity of this cell will be examined. This will be done by comparing oxygen uptake and metabolism, and lipid peroxidation in control and lipidotic cells. The activities of a number of cellular enzymes involved in the protection against superoxide anion, hydrogen peroxide and lipid peroxication will also be measured. Decreases in their levels in the lipidotic cells would indicate that they may be less able to tolerate the generation of reactive oxygen metabolites. Finally, studies will be performed which will examine whether changes in lipidotic macrophages from chlorphentermine-treated rats are specific for this drug or are generalized responses to the induction of phospholipidosis by amphiphilic drugs. This will be done by studying the effects of the administration of iprindole and chlorcyclizine on certain biochemical and cellular properties of the alveolar macrophage.